The main goal of this proposal is to understand the transcriptional control of homeostatic and antigen-driven proliferation of na[unreadable]ve and memory CD8 T cells aiming to improve the immunity of young and aged individuals by increasing the pool of memory T cells. The immune system keeps a subset of antigen-specific memory T cells to ensure long-lasting protection from subsequent infections. The intrinsic factors in the nuclei required for the generation and maintenance of memory T cells have not been extensively studied yet. Our preliminary data show that the transcription factor ELF4 controls proliferation of na[unreadable]ve T cells leading to increased numbers of memory-like T cells over time. Thus, Elf4-null mice represent a novel model to study in vivo how a deregulated cell cycle could change the response to environmental signals. The specific goal of this proposal is to understand how ELF4 regulate the development and maintenance of antigen-experienced memory T cells. Our hypothesis is that ELF4 restricts the cell-cycle entry of na[unreadable]ve and memory T-cells by regulating the expression of cell cycle inhibitors, limiting the number of memory precursors and therefore modulating the size and tissue distribution of the memory pool over time. The specific aims of this proposal are: Aim 1: Study the antigen-dependent proliferation leading to memory T cells using immunization with dendritic cells and develop an RNAi-based chimera model to conditionally regulate endogenous Elf4 expression at will during the different phases of T cell response (expansion ->contraction ->memory). Aim 2: Examine the role of ELF4 in the homeostatic maintenance of memory T cells using antigen-experienced memory T cells induced by infection with a intracellular bacteria. Aim 3: Develop a loss-of-function mouse model of a cell cycle inhibitor regulated by ELF4 to study its role in the generation and maintenance of memory T cells. Public Health Relevance Statement: The immune responses acquired throughout life are imprinted in "memory T cells" to ensure a long lasting immunity. Knowing how memory T cells are developed and maintained over time at a molecular level is essential to improve vaccination protocols and to protect young and old population from recurrent infections such as influenza. This project will also aid to understand survival of functional memory T cells in the site of primary infection to enhance recall responses.